Local drug delivery devices and methods for treating cancer

ABSTRACT

Drug-eluting devices and methods for the treatment of tumors of the pancreas, biliary system, gallbladder, liver, small bowel, or colon, are provided. Methods include deploying a drug-eluting device having a film which includes a mixture of a degradable polymer and a chemotherapeutic drug, wherein the film has a thickness from about 2 μm to about 1000 μm, into a tissue site and releasing a therapeutically effective amount of the chemotherapeutic drug from the film to treat the tumor, wherein the release of the therapeutically effective amount of the drug from the film is controlled by in vivo degradation of the polymer at the tissue site.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.14/250,025, filed Apr. 10, 2014, which claims priority to U.S.Provisional Patent Application No. 61/810,543, filed Apr. 10, 2013,which are incorporated by reference herein.

TECHNICAL FIELD

The present disclosure is generally in the field of drug deliverydevices and methods, and more particularly relates to implantabledevices and methods providing controlled release of drug locally totissue sites where needed, such as in treating tumors of the pancreas,biliary system, gallbladder, liver, small bowel, or colon.

BACKGROUND

Pancreatic cancer is the fourth most common cause of cancer-relateddeath in the United States. (American Cancer Society Statistics, 2011).Ninety-four percent of patients diagnosed with pancreatic cancer diewithin 5 years of the diagnosis, giving pancreatic cancer the highestmortality rate of all major cancers. While a fifty-five percent increasein new pancreatic cancer cases is predicted over the next two decades,no early detection methods have been developed.

The most common form of pancreatic cancer is ductal adenocarcinoma(PDAC), which accounts for ninety-five percent of all pancreatic tumors.The vast majority of PDAC patients suffer from significant morbidityfrom local tumor growth, which include symptoms of abdominal pain,anorexia, nausea, vomiting, and jaundice. Unfortunately, the majority ofdiagnosed PDAC is not resectable, which limits therapies for localdisease control to a combination of radiation and chemotherapy.

Despite the development of new anti-cancer agents, PDAC remains highlyrefractory to systemically delivered therapies, due in part to (i)impaired drug delivery caused by lack of local vasculature that limitsdrug distribution within the tumor and (ii) a fibrotic response to thetumor cells that restricts penetration of drug. These factors cannot beovercome by systemic therapies because of limited local residence anddose related toxicities that prevent use of high drug concentrations.For example, gemcitabine therapy has a ten percent response rate, andthose regimens that increase response also increase systemic toxicity(e.g., FOLFIRINOX regimen has a thirty-one percent response rate butwith greater systemic toxicity). (Conroy, T. et al, New England J.Medicine, 364:1817-25 (2011)).

Accordingly, there remains a need for improved methods and devices forcancer therapy, in particular for reducing the problems associated withsystemic administration of chemotherapeutic agents to treat tumors. Itwould be desirable to have better approaches for treating tumors in thepancreas and other intraperitoneal sites, the biliary system,gallbladder, liver, small bowel, and colon.

SUMMARY

In one aspect, methods are provided for treating a tumor of thepancreas, biliary system, gallbladder, liver, small bowel, or colon. Themethods include (i) deploying a drug-eluting device into a tissue siteof a patient in need of treatment, the device including a film whichincludes a mixture of a degradable polymer and a chemotherapeutic drug,wherein the film has a thickness from about 2 μm to about 1000 μm, and(ii) releasing a therapeutically effective amount of thechemotherapeutic drug from the film to the tissue site to treat thetumor, wherein the release of the therapeutically effective amount ofthe chemotherapeutic drug from the film is controlled by in vivodegradation of the polymer at the tissue site.

In another aspect, drug-eluting devices are provided for the treatmentof a tumor of the pancreas, biliary system, gallbladder, liver, smallbowel, or colon. The devices include a film having a thickness fromabout 2 μm to about 1000 μm and including a mixture of a degradablepolymer and a chemotherapeutic drug, wherein the device is configuredfor deployment into a tissue site of a patient, the film beingconfigured to provide controlled release, by in vivo degradation of thepolymer at the tissue site, of a therapeutically effective amount of thechemotherapeutic drug to the tissue site to treat the tumor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of one embodiment of a drug-eluting devicein the form of a stent.

FIG. 1B is a cross-sectional view of one of the struts of the stent ofFIG. 1A.

FIG. 2A is a perspective view of one embodiment of a drug-elutingdevice.

FIG. 2B is a cross-sectional view of the drug-eluting device of FIG. 2A.

FIG. 3A is a perspective view of one embodiment of a drug-elutingdevice.

FIG. 3B is a cross-sectional view of the drug-eluting device of FIG. 3A.

FIG. 4 is a process diagram illustrating one embodiment of a method formaking drug-eluting devices.

FIG. 5 is a scanning electron microscopic photograph of a drug-elutingdevice.

FIG. 6 is a scanning electron microscopic photograph of a drug-elutingdevice.

FIG. 7 is a diagram illustrating the treatment of tumor cells over timewith a drug-eluting device.

FIG. 8 is a graph showing the amount of paclitaxel released over timefrom a drug-eluting device in vitro.

FIG. 9 is a graph showing the percentage of paclitaxel released overtime from drug-eluting devices with varying film compositions in vitro.

FIG. 10 is a graph showing the amount of paclitaxel released over timefrom drug-eluting devices with varying film compositions in vitro.

FIG. 11 is a set of micrographs showing five of the six pancreaticadenocarcinoma cell lines (PDAC 1-6) used in in vivo studies.

FIG. 12 is a graph showing the optical density over time of five of thesix pancreatic adenocarcinoma cell lines (PDAC 1-6) used in in vivostudies.

FIG. 13 is a graph showing the cell viability at various drugconcentrations of five of the six pancreatic adenocarcinoma cell lines(PDAC 1-6) used in in vivo studies.

FIG. 14 is a graph showing the relative tumor growth over time of PDAC-3when treated with a paclitaxel-eluting device versus when treated withpaclitaxel intravenously.

FIG. 15 is a graph showing the relative tumor growth over time of PDAC-6when treated with a paclitaxel-eluting device versus when treated withpaclitaxel intravenously.

FIG. 16 is a graph showing the relative tumor reduction of adrug-eluting device versus intravenous drug treatment for PDAC-3 andPDAC-6.

FIG. 17 is a graph showing the weight of a pancreas treated with adrug-eluting device versus intravenous drug treatment for PDAC-3 andPDAC-6.

FIG. 18 is a graph showing the average tissue/drug spatial correlationof pancreatic sites treated with a drug-eluting device versusintravenous drug treatment.

DETAILED DESCRIPTION

Improved local drug delivery systems have been developed which arecapable of effectively delivering chemotherapeutic agents to tumors inhigher doses compared to IV systemic administration. The systemssurprisingly were found to be capable of achieving five times the drugpresence and distribution within the tumor as compared to IV therapy inan animal model. Accordingly, these devices and methods advantageouslybypass known therapeutic obstacles and may provide local delivery ofhigh levels of a conventional, as well as novel, cytotoxic agents foreffective tumor cell cytotoxicity and minimal bystander cell toxicity.

The methods and devices utilize a mixture of a degradable polymer and achemotherapeutic drug, wherein the mixture is in the form of a filmhaving a thickness from about 2 μm to about 1000 μm and wherein the filmis configured to provide controlled release, by in vivo degradation ofthe polymer at the tissue site, of a therapeutically effective amount ofthe chemotherapeutic drug to the tissue site of the tumor. For instance,the methods and devices may be used to locally treat tumors of thepancreas, biliary system, gallbladder, liver, small bowel, or colon,among others. In certain embodiments, the device is deployed into apancreatobiliary or intraperitoneal tissue site. For example, thesedevices may be placed in the pancreatobiliary tree to direct the drug toits target and prevent closure of the pancreatobiliary tract by cancercell growth. As such, these methods and devices may also be suitable fortreatment of other cancers of the biliary tree including but not limitedto cholangiocarcinoma, gallbladder cancer, lymphoma, and metastatictumors.

Drug-Eluting Devices

In certain embodiments, as shown in FIGS. 1-3, a drug-eluting device forthe treatment of a tumor of the pancreas, biliary system, gallbladder,liver, small bowel, or colon, is provided. The device includes a filmhaving a thickness from about 2 μm to about 1000 μm and including amixture of a degradable polymer and a chemotherapeutic drug. The deviceis configured for deployment into a tissue site of a patient, the filmbeing configured to provide controlled release, by in vivo degradationof the polymer at the tissue site, of a therapeutically effective amountof the chemotherapeutic drug to the tissue site to treat the tumor. Forexample, the tissue site may be a biliary or pancreatic duct.

As used herein, the term “film” refers to a relatively thin coating,layer, patch, or sheet-like structure formed at least in part of themixture of the degradable polymer and the chemotherapeutic drug. As isdescribed in more detail throughout this disclosure, the film may beself-supporting or may be adhered or otherwise disposed on a supportingsubstratum. The film may be flexible or rigid. In certain embodiments,the film has a thickness from about 5 μm to about 500 μm. In oneembodiment, the film has a thickness of less than about 100 μm. In oneembodiment, the film has a thickness from about 5 μm to about 100 μm.However, it should be understood that the film thickness rangesdisclosed herein are merely exemplary, and that other film thicknesses,including thicknesses above about 1000 μm, may be used without departingfrom the spirit of the present disclosure.

The film includes a mixture of a degradable polymer and achemotherapeutic drug and is configured to provide controlled release ofthe drug by in vivo degradation of the polymer at the tissue site. Inone embodiment, the mixture includes from about 1 weight percent toabout 10 weight percent of the chemotherapeutic drug. In one embodiment,the film is configured to release drug in an amount of about 0.5 pg toabout 1000 mg per week.

For example, the polymer may be any suitable biodegradable polymer knownin the art. Examples of suitable polymeric materials include syntheticpolymers selected from poly(amides), poly(esters), poly(anhydrides),poly(orthoesters), polyphosphazenes, pseudo poly(amino acids),poly(glycerol-sebacate), copolymers thereof, and mixtures thereof. Forexample, a suitable polymer may be formed from poly(lactic acids),poly(glycolic acids), poly(lactic-co-glycolic acids),poly(caprolactones), and mixtures thereof.

In a preferred embodiment, the degradable polymer ispoly(lactic-co-glycolic acid) (PLGA). For example, the film may containPLGA copolymers with or without ester terminations, including but notlimited to PLGA 50:50, 75:25, and 65:35. Advantageously, PLGA and otherdegradable polymers may provide the ability to modulate the drug releasekinetics of the film, as compared to certain other polymeric materials,such as polyurethane, with which controlling release kinetics is moredifficult.

In one embodiment, the degradable polymer is a hydrolytically degradablepolymer. That is, the polymer undergoes hydrolytic bond cleavageresulting in polymer degradation. For example, release of the drug fromthe film may be controlled by non-enzymatic, hydrolytic degradation ofthe polymer at the tissue site. Such a drug release kinetics profile maybe particularly desirable for implantation sites, such aspancreatobiliary sites, where the presence of enzymes is high. Indeed,the pancreas is one of the most challenging organs for designing andmanufacturing a dedicated drug-eluting platform because of itsanatomical position along with its massive production of digestiveenzymes.

Prior attempts were made to design a pancreatobiliary drug-eluting stentusing a polyurethane based method to treat PDACs. (see Lee et al., “TheEffect on Porcine Bile Duct of a Metallic Stent Covered with aPaclitaxel-Incorporated Membrane,” Gastrointest. Endosc. 61(2):296-301,February 2005). However, these devices were limited in their ability tocontrol polymer erosion and thus maintain adequate sustained drugrelease. Specifically, erosion of the polyurethane allowed the formationof superficial cracks in the polymer, thus causing unpredictable drugrelease. Because a reliable and predictable in vivo polymerdegradation/drug release profile is important, that earlier work failedto show improvements in the clinical outcome. Accordingly, it isdesirable that hydrolytic bulk degradation of the polymer occurs via thesurrounding fluids imbibing the coating layer, to trigger bulkdegradation and initiate drug release, without causing superficialcracks. As described in more detail herein, such controllable hydrolyticbulk degradation without cracking has been observed with PLGA.

In one embodiment, the degradable polymer includes a radiation-sensitivepolymer configured to release the drug in response to the patient beingexposed to radiation.

As is discussed in further detail in the Examples section, the film maybe prepared by solvent evaporation in a solution having a concentrationof about 5 to about 40 percent weight by volume of the polymer. Incertain embodiments, the film is prepared by solvent evaporation in asolution having a concentration of about 10 to about 30 percent weightby volume of the polymer.

The film optionally may include one or more pharmaceutically acceptableexcipients. For example, the one or more pharmaceutically acceptableexcipients may be combined in the mixture with the degradable polymerand the chemotherapeutic agent.

The chemotherapeutic drug may be any drug formulation effective to treatcancer by inhibiting the growth and/or invasiveness of malignant cellsand/or inducing cytotoxicity by apoptosis or necrosis of malignantcells. The chemotherapeutic agent may be a taxane or platinum drug knownfor use in treating cancer. In certain embodiments, the chemotherapeuticdrug is selected from the group consisting of paclitaxel, gemcitabine,nab-paclitaxel, 5-fluorouracil, oxaliplatin, irinotecan, andcombinations thereof. In certain embodiments, the chemotherapeutic drugincludes an MEK inhibitor, a PI3K inhibitor, a Hedgehog inhibitor, a Wntinhibitor, or a combination thereof. In certain embodiments, the drugincludes an agent that interferes with the mTOR or NfKb pathways. Incertain embodiments, the chemotherapeutic drug is a drug, such as anovel therapeutic, that displays poor systemic delivery or dose limitedtoxicities. For example, the chemotherapeutic drug may be a phase I drugthat was promising in preclinical trials, but was found to be poorly ornot tolerable with systemic dosing. The chemotherapeutic drug may beselected from new classes of therapies, such as siRNA-Alnylam typetherapies, where delivery has traditionally been rate-limiting.

In a preferred embodiment, the chemotherapeutic drug is paclitaxel andthe degradable polymer is poly(lactic-co-glycolic acid). For example,for such a film composition, the therapeutically effective amount may beat least about 1 mg/day of the paclitaxel. In one embodiment, thetherapeutically effective amount may be a mean average amount of from 5mg/day to 125 mg/day of the paclitaxel.

In certain embodiments, bulk degradation of the film is tunable from afew days to several months (e.g., 12 months or more). In one embodiment,the film is configured to degrade within a period of about 1 day toabout 12 months after deployment, for example between 30 and 120 days.In one embodiment, the film is configured to degrade within a period ofless than 2 years.

In certain embodiments, the device is configured to release thechemotherapeutic drug according to a defined release kinetics profile.For example, the release kinetics profile may include a delay periodfrom about 1 day to about 14 days after deploying of the device into thetissue site. For example, during the delay period a sub-therapeuticallyeffective amount of the drug may be released (e.g., by diffusion of drugpresent on or at the surface of the film). The delay advantageouslyfacilitates at least some healing of normal tissues at the deploymentsite (e.g., adjacent to the tumor) before release of exposure to (therelatively larger) therapeutically effective of amounts of thechemotherapeutic agent. This release profile reduces the risk ofinfection, perforation, bleeding, and other complications. That is, thedelay period avoids a burst release and allows enough time for thepatient to recover from surgery before the chemotherapeutic drug isreleased.

After the delay, or slow release, period, acceleration of release to atherapeutically effective level occurs. For example, the film may beconfigured to provide an initial release rate of the chemotherapeuticdrug which is substantially linear, following the delay period. In oneembodiment, the release of the therapeutically effective amount of thechemotherapeutic drug, after the delay period, has an initial releaserate that is substantially linear for at least 3 days.

In certain embodiments, the therapeutically effective amount of the drugis released over a treatment period of about 10 days to about 1 year. Inone embodiment, a therapeutically effective amount of drug is releasedover a treatment period from about 10 days to about 90 days. In oneembodiment, a therapeutically effective amount of drug is released overa treatment period of about 30 days. In certain embodiments, an initialrelease of drug at a substantially linear release starts from about day5 up to about 60 days. Thus, a high concentration of the drug is locallyreleased over a short period of time. This aggressive treatment regimeattacks the tumor and makes it regress in the shortest time possible.

The release kinetics profile of the film may be tailored based on theselection of the degradable polymer. For example, PLGA displays abiphasic release profile, as diffusion and degradation provide twodifferent release peaks. Accordingly, PLGA displays a highly tunablesustained release profile including an initial lag or delay, an initiallinear release period, then a release plateau.

These devices can be fabricated in various shapes and sizes to adapt todifferent deployment sites and methods. For example, the tissue site maybe a pancreatobiliary tissue site, in which case a stent or tubulardevice may be preferred, or the tissue site may be an intraperitonealtissue site, in which case a mesh or patch-type device may be preferred.The device may be implanted in an open surgical procedure orlaparoscopically.

In certain embodiments, the device further includes a biocompatiblesubstratum to which the film is adhered or otherwise fixed. For example,the substratum may be any suitable structure for implantation in apatient at a desired tissue site. For example, the substratum may be astent, tube, patch, or mesh structure. The substratum may be flexible orrigid. The substratum may be made of any suitable material orcombination of materials. For example, the substratum may include ametal, a polymer, or a ceramic material. In certain embodiments, thesubstratum includes stainless steel alloy, cobalt chromium alloy,nitinol, platinum alloy, titanium alloy, silicone, expandedpolytetrafluoroethylene (ePTFE), or polyethylene.

In certain embodiments, the device may be configured to be inserted intoa biliary or pancreatic duct of a patient. The term “configured” in thisembodiment means that the device has suitable dimensions, geometry,materials of construction, flexibility/softness (e.g., durometer value)for insertion and use within a biliary or pancreatic duct of a patient.For example, the device may be configured to prevent closure of apancreatic duct in which it is deployed. For example, a drug-elutingstent may reduce stent re-occlusion, which is a common complication forpancreatic and biliary cancer patients who receive stents for biliaryobstructions. One embodiment is shown in FIGS. 1A-1B. Drug-eluting stent100 includes struts 102 having a film 106 disposed on strut substratum104.

In various embodiments, the stent may be a balloon expanding orself-expandable stent, or the stent may be non-expanding. The stent mayor may not have open lattice structure. That is, the stent may or maynot have one or more apertures in the sidewall. The stent also may ormay not have anchoring flaps at their ends. In one embodiment, the stenthas a length of about 0.5 cm to about 18 cm and a diameter of about 2 mmto about 30 mm. For example, a stent may have a length of about 3 cm toabout 18 cm and a diameter of about 2 mm to about 10 mm.

As shown in FIGS. 3A-3B, device 300 includes a substratum patch 304having a film 306 disposed thereon. The patch may be rigid or flexible.The substratum may also be a flexible or rigid mesh on which the film isdisposed. In certain embodiments, the device is configured to beimplanted directly onto the tumor.

In certain embodiments, as shown in FIGS. 2A-2B, the device 200 includesfilm 206, which is self-supporting, and is not supported by asubstratum. The device may be a flexible/foldable or rigid patch-typedevice. In certain embodiments, the device is configured to be implanteddirectly onto the tumor. Other substratum constructions and geometriesare also envisioned.

In certain embodiments, the film may be adhered to or disposed on thesubstratum by spray coating, dip coating, sintering, or any form ofadhesion or coating on any aspect or part of the substratum. Othercoating techniques may be used and are known to those of ordinary skillin the art. In certain embodiments, the film is adhered to thesubstratum in a uniform thickness of about 2 to about 500 μm. Forexample, the film may have a uniform thickness of about 10 to about 100μm. In certain embodiments, the film is a homogenous, smooth, nonporouscomposition having a uniform thickness. The thickness may be selectedbased on the desired degradation/release kinetics and the total drugpayload needed, for example.

In other embodiments, the coating may be deposited in an array ofdiscrete regions in or on the substratum. In one example, the substratummay have a plurality of through-holes or concave regions which serve asreservoirs and are loaded with the drug coating material.

Methods of Treatment

In certain embodiments, methods of treating a tumor of the pancreas,biliary system, gallbladder, liver, small bowel, or colon, are provided,including: (i) deploying a drug-eluting device into a tissue site of apatient in need of treatment, the device having a film which includes amixture of a degradable polymer and a chemotherapeutic drug, wherein thefilm has a thickness from about 2 μm to about 1000 μm, and (ii)releasing a therapeutically effective amount of the chemotherapeuticdrug from the film to the tissue site to treat the tumor, wherein therelease of the therapeutically effective amount of the chemotherapeuticdrug from the film is controlled by in vivo degradation of the polymerat the tissue site. The drug-eluting device may include any of thedevice, film, polymer, drug, substratum, or other features describedherein, as well as alternatives thereof, which are also meant to fallwithin the scope of this disclosure.

In one embodiment, release of the therapeutically effective amount ofthe chemotherapeutic drug has a substantially linear rate of releasefollowing a delay period of from about 1 day to about 14 days afterdeploying of the device into the tissue site. For example, the delayperiod may be from about 2 to about 4 days. In certain embodiments, asub-therapeutically effective amount of the drug is released during thedelay period.

In one embodiment, the chemotherapeutic drug is paclitaxel and thedegradable polymer is poly(lactic-co-glycolic acid). For example, forsuch a film composition, the therapeutically effective amount may be atleast about 1 mg/day of the paclitaxel. In one embodiment, thetherapeutically effective amount may be a mean average amount of from 5mg/day to 125 mg/day of the paclitaxel. In one embodiment, atherapeutically effective amount of drug is released over a treatmentperiod from about 10 days to about 90 days. In one embodiment, thedegradable polymer is configured to degrade within a period from about 1day to about 12 months after deployment.

In embodiments in which the device includes a substratum, deploying thedevice may include inserting the device into a biliary or pancreaticduct of the patient or implanting the device directly onto the tumor. Inone embodiment, the substratum is a balloon-expanding stent and the stepof deploying the device includes inflating a balloon to expand thestent.

The drug-eluting devices and methods described herein may be usedtogether with current systemic chemotherapy, external radiation, and/orsurgery to prolong survival in patients. These devices and methodsadvantageously provide local delivery of chemotherapy for treatment ofpancreatobiliary cancers. It is believed that modification of known drugdelivery barriers (i.e., hypovascularity and significant desmoplasticstromal response) can sensitize pancreatic primary tumor cells tostandard doses of cytotoxic therapies. Therefore, these devices andmethods may utilize conventional cytotoxics with efficacy in pancreaticcancer, as well as novel treatment agents that cannot be tolerated insystemic administration.

The drug-eluting devices and methods described herein may be more fullyunderstood in view of the following examples.

EXAMPLES

Using in vitro and in vivo animal studies, it was determined that afilm-based device configured to release chemotherapeutic agents can beused to locally treat adenocarcinomas.

In Vitro Studies

Drug-polymer film coated substratum samples were prepared according tothe process shown in FIG. 4. Specifically, a solution of paclitaxel inacetone 400 was combined with a solution of PLGA in acetone 402 to forma solution of paclitaxel and PLGA in acetone 404. This solution waspoured onto a stainless steel disc 406 and then the solvent wasevaporated to form sample 408 having a drug-polymer film 412 coated onthe substratum 414.

In one example, PLGA 50:50 (Resomer® RG502) was dissolved in acetone atseveral concentrations: 5%, 10%, and 20% w/v, and combined withsolutions containing 200 μg paclitaxel (Invitrogen®). EachPLGA-paclitaxel solution was stirred and poured onto an AISI 316Lstainless steel 6 mm disc. To study the drug release of the devices, aratio 1:250 of fluorescent drug was added to the solution, and the discwas put in PBS and incubated at 37° C. At selected times, an aliquot ofsupernatant was analyzed and replaced by fresh media. FIG. 8 shows theamount of paclitaxel released from the sample made with 10% w/v PLGA.This sample showed a delayed onset of the release kinetics and asustained ongoing release after ten days.

In another example, two different samples were tested: stainless steeldiscs coated with PED_10_200 and PED_20_400, differing one from theother in PLGA concentration (10 or 20% w/v) and paclitaxel amount (200or 400 μg). FIGS. 9 and 10 show the percent and amount of paclitaxelreleased over time. It was observed that the concentration of thepolymer in the film could be used to tune the release profile of thedrug.

The samples were also fully characterized in terms of weight,morphology, and thickness of the film coating. Surface chemicalcharacterization was carried out by analysis in dispersion of energy(EDAX, Oxford mod. INCA 200) using scanning electron microcopy (SEM,Leica 420). The electron microscopy analysis showed a homogeneous,smooth, nonporous PLGA layer coating the metallic surface. Morphologicaldepictions showed a uniform surface appearance, with no cracks orbubbles observed, and homogeneous distribution of paclitaxel. Analyseswere also performed at different locations along the coating surfacewhere each measurement confirmed the presence of polymeric atomicelements at the expected stoichiometric ratio.

As illustrated in FIGS. 5-6, thickness was calculated using the SEMsoftware revealing a constant value in all the investigated locations.FIG. 5 depicts the thickness (˜70 μm), uniformity, and homogeneity ofthe PED_10_200 film on a 316L stainless steel disc having a thickness ofapproximately 500 μm. FIG. 6 depicts the thickness (˜90 μm), uniformity,and homogeneity of the PED_20_400 film on a 316L stainless steel dischaving a thickness of approximately 500 μm. It was found that thethickness of the coating layer may be modulated through an opportuneselection of the polymer concentration. This observation is criticalgiven the tight relationship of PLGA degradation kinetics, and thereforethe elution rate of paclitaxel, as a function of thickness.Specifically, this methodology resulted in a platform technologyensuring similar outcomes for different formulations, as highlighted bythe small difference in thickness between PED_10_200 and PED_20_400 (seeFIGS. 5-6, 9-10).

In summary, controlled release of fluorescently-labeled paclitaxellasting for more than one month was achieved from samples where therelease kinetics were highly tunable using different ratios of PLGA andpaclitaxel. In particular, a delayed release buffer period could bemodulated with increasing polymer concentration in the organic phase.This initial formulation-dependent delay could be tailored to allowadequate healing time for patients following surgical implantation.After this healing phase, the device would release its drug payload at asteady and predictable rate, including an initially linear releaseperiod. Moreover, the device can be designed to release differentamounts of chemotherapeutic agent with similar kinetics. By doublingboth the drug content and polymer concentration, the film formulationswere tuned to accomplish an initial linear release of paclitaxel (seeFIGS. 8-10). Additionally, the dose released increase and the in vitrotime of treatment increased from 45 days (for the lower dose) to 60 days(for the higher dose) (see FIGS. 8-10).

For implanted devices, biocompatibility and sterility is a foremostrequirement. Therefore, the interaction between UV sterilized devicesand Endothelial Cell culture overtime was also tested. The coated discswere sterilized overnight under UV. Cells in contact with the sterilizedcoated disc were observed to be vital and displayed normal growth andmorphology. No bacterial or fungal contamination was found after 3 daysof co-culture. Moreover, incubation of the samples in aqueous mediaverified great adherence to the metallic substratum as shown by thepresence of coating at later time points and homogenous polymerdegradation.

The in vitro studies show the ability to achieve a polymeric filmcoating on a substratum and to optimize the interface properties,adhesion, degradation, and drug release kinetics. By changing processingconditions (e.g., polymer:solvent ratio, amount of drug, evaporationtime, evaporation condition), it is possible to modulate thickness ofthe coating layer, and thereby tailor the degradation kinetics of thefilm. For example, because the release profile is a function of polymerthickness, the kinetic profiles of these devices may be easily tailored,such that a device's pharmaceutical activity can be selected by simplyadjusting coating parameters to match the need of the patient.

In Vivo Studies

As shown in FIGS. 11-13, six newly established pancreatic adenocarcinomacell lines (PDAC 1-6) were generated from metastatic ascites in patientsenrolled in an IRB approved protocol at Massachusetts General Hospital(five of the six PDAC lines are shown). The cell lines wereorthotopically injected in NOD/SCID/γc immunodeficient mice to identifythe optimal xenograft tumor model system for testing the drug elutingpolymer device.

The orthotopic pancreatic xenografts formed tumors in mice with varyinghistologies. For example, cell line PDAC-6 developed the mostdesmoplastic response compared to other cell lines in vivo.Specifically, a Hematoxylin and Eosin stained PDAC-6 orthotopicxenograft showed epithelial tumor cells surround by desmoplastic stromalresponse. PDAC-3 was mesenchymal in appearance, migratory, andchemorsistant, while PDAC-6 was epithelial in appearance, has a highlevel of stroma, shows no migration, and is chemosensitive. Thus, thepatient-derived cell lines reflect the variability of PDAC patients'response to chemotherapy, showing different in vitro and in vivopaclitaxel sensitivity.

A paclitaxel eluting device (PED) was implanted into the mice at week 4.The results of the mouse xenograft studies are shown in FIGS. 14-18.Overall, a decrease in relative tumor growth was observed in both thePDAC-3 and PDAC-6 cell lines with the use of a drug eluting device. Thatis, the mice tumors model data shows efficacy of the local drug deliveryplatforms for treating pancreatic cancer. FIG. 7 shows the PDAC cellreduction mechanism of the polymer-drug film 706. Specifically, uponimplantation at a tissue site, the film 706, which is disposed onsubstratum 704 and includes a chemotherapeutic drug 707 and a degradablepolymer 705, the polymer 705 degrades, triggering release of the drug707 to the site. This hinders growth of the PDAC cells 710 at the tissuesite, resulting in dead tumor cells 712.

In FIGS. 14-18, the relative efficacy of the drug-eluting device(PED_20_400) was compared to intravenous (IV) systemic delivery,utilizing fluorescently-labeled paclitaxel to measure its distributioninside pancreatic xenografts. Higher intratumoral paclitaxel presenceand a greater tumor growth inhibition were observed in mice having theimplanted PED compared to mice treated with systemic administration ofpaclitaxel. Although neither of the cell lines was exposed to paclitaxelbefore, the PDAC-6 xenografts displayed an early tumor response whilethe PDAC-3 tumors needed roughly two weeks to show a clear tumor growthinhibition, recapitulating the in vitro paclitaxel sensitivity profiles.As shown in FIG. 16, the paclitaxel-eluting devices showing a 2 to 12fold increase in tumor reduction as compared to systemic IV therapy.

Extracted tumor masses from PED-bearing mice macroscopically showedpresence of fluorescent dye when observed under a dissecting microscope.To quantify intratumoral drug distribution, serial sections of the tumorperpendicular to the PED were imaged by quantitative confocalmicroscopy. Paclitaxel tissue retention was markedly higher in tumorstreated with the PED compared to intravenous dosing. Tissue penetrationwithin the tumor was quantified by line scans starting from the entrysite for paclitaxel (PED—tumor/device interface; IV—vessels).Remarkably, paclitaxel penetration depth extended up to 400 microns forthe PED, while IV administration was limited to presence only in a 10micron radius around the vessels. Moreover, as shown in FIG. 18, bymapping the images with a matlab algorithm, we evaluated that targetedrelease allowed for increased paclitaxel/tumor co-localization with apercentage area almost 5 fold higher than in the case of systemic IVdelivery. That is, the paclitaxel-eluting devices resulted in 5 timesthe drug presence and distribution within the tumor as compared to IVtherapy.

In summary, a degradable polymer film was developed to provide a highlytunable sustained release of drug in a device suitable for implantationin a pancreatic orthotopic xenograft mouse model. This device was welltolerated in all mice and surprisingly demonstrated significant tumorresponse in two different human PDAC cell line xenografts compared toequivalent systemic dosing. Moreover, significantly higher tissuepenetration of drug was observed using the PED as compared to systemicintravenous dosing. This higher delivery was achievable without anyadverse effects to the mice and with notable reduction of viable tumormass for the pancreatic cell line xenografts.

These results highlight the potential of these devices to deliver highdoses of cytotoxic agents as well as novel therapeutics providing a newmodality to treat tumors by bypassing inherent drug delivery barriers.Specifically, these results show that effective local delivery ofconventional chemotherapeutic agents can overcome intrinsic PDACchemoresistance, opening new therapeutic strategies to improve theoutcomes of such patients. Utilizing a degradable polymer, amulti-purpose drug-eluting device can be designed as described herein tolocally deliver high payloads of cytotoxic agents and reach higherintratumoral concentrations not achievable with systemic administrationdue to dose-limiting toxicity. Moreover, releasing sustained localconcentrations of chemoactive agents may increase the longevity of thedevice and inhibit local tumor progression. This would significantlyimprove the ability to palliate biliary obstruction symptoms, reduce thenumber of re-stenting procedures, and improve the quality of life inpatients.

Furthermore, because PDAC patients may respond very differently tochemotherapy, it is advantageous that these devices can be personalizedto release different amounts of drugs at a desired release kineticprofile, to maximize the cytotoxic effects of current or futureanti-neoplastic agents and minimize systemic toxicity to achieve agreater tumor response and patient survival.

Modifications and variations of the methods and devices described hereinwill be obvious to those skilled in the art from the foregoing detaileddescription. Such modifications and variations are intended to comewithin the scope of the appended claims.

We claim:
 1. A method of treating a tumor of the pancreas, biliarysystem, gallbladder, liver, small bowel, or colon, comprising: deployinga drug-eluting device into a biliary or pancreatic duct of a patient inneed of treatment, the device comprising: a film which forms an outersurface of the device and comprises a mixture of a degradable polymerconsisting of poly(lactic-co-glycolic acid) and a chemotherapeutic drugin which the chemotherapeutic drug is homogenously distributed in thepoly(lactic-co-glycolic acid) via solvent evaporation of a solution ofthe chemotherapeutic drug and the poly(lactic-co-glycolic acid) whereinthe film is formed from a solution containing poly(lactic-co-glycolicacid) in an amount of from 10 to 30 percent weight by volume, whereinthe film has a uniform thickness from 10 μm to 100 μm and is configuredto provide release of the chemotherapeutic drug via degradation of thepoly(lactic-co-glycolic acid); and a biocompatible substratum to whichthe film is adhered, the substratum comprising a stent; and releasing atherapeutically effective amount of the chemotherapeutic drug from thefilm to treat the tumor, wherein the release of the therapeuticallyeffective amount of the chemotherapeutic drug from the film iscontrolled by in vivo degradation of the poly(lactic-co-glycolic acid)in the biliary or pancreatic duct, wherein the release of thetherapeutically effective amount of the chemotherapeutic drug from thefilm follows a delay period of from about 2 days to about 14 days afterdeploying the device into the biliary or pancreatic duct, wherein asub-therapeutically effective amount of the drug or no drug is releasedduring the delay period, and wherein the delay period is controlledsolely by the in vivo degradation of the poly(lactic-co-glycolic acid)in the biliary or pancreatic duct.
 2. The method of claim 1, wherein therelease of the therapeutically effective amount of the chemotherapeuticdrug, after the delay period, has an initial release rate that issubstantially linear for at least 3 days.
 3. The method of claim 1,wherein the delay period is from 2 to 4 days.
 4. The method of claim 1,wherein the chemotherapeutic drug is selected from the group consistingof paclitaxel, gemcitabine, nab-paclitaxel, 5-fluorouracil, oxaliplatin,irinotecan, and combinations thereof.
 5. The method of claim 1, whereinthe chemotherapeutic drug is paclitaxel.
 6. The method of claim 5,wherein the therapeutically effective amount of the paclitaxel releasedis at least about 1 mg/day.
 7. The method of claim 5, wherein thetherapeutically effective amount of the paclitaxel released is at a meanaverage amount of from 5 mg/day to 125 mg/day.
 8. The method of claim 5,wherein the therapeutically effective amount of paclitaxel is releasedover a treatment period from about 10 days to about 90 days.
 9. Themethod of claim 1, wherein the mixture comprises from about 1 wt % toabout 10 wt % of paclitaxel.
 10. The method of claim 1, wherein thepoly(lactic-co-glycolic acid) is configured to degrade within a periodfrom about 2 days to about 12 months after deployment.
 11. A method oftreating a tumor of the pancreas, biliary system, gallbladder, liver,small bowel, or colon, comprising: deploying a drug-eluting device intoa tissue site of the pancreas, biliary system, gallbladder, liver, smallbowel, or colon of a patient in need of treatment, the devicecomprising: a film which forms an outer surface of the device andcomprises a mixture of a degradable polymer consisting ofpoly(lactic-co-glycolic acid) and a chemotherapeutic drug in which thechemotherapeutic drug is homogenously distributed in thepoly(lactic-co-glycolic acid), via solvent evaporation of a solution ofthe chemotherapeutic drug and the poly(lactic-co-glycolic acid) whereinthe film is formed from a solution containing poly(lactic-co-glycolicacid) in an amount of from 10 to 30 percent weight by volume, whereinthe film has a uniform thickness from 10 μm to 100 μm, and is configuredto provide release of the chemotherapeutic drug via degradation of thepoly(lactic-co-glycolic acid); and a biocompatible substratum to whichthe film is adhered, the substratum comprising a stent; and releasing atherapeutically effective amount of the chemotherapeutic drug from thefilm to treat the tumor, wherein the release of the therapeuticallyeffective amount of the chemotherapeutic drug from the film iscontrolled by in vivo degradation of the poly(lactic-co-glycolic acid)in the tissue site, wherein the release of the therapeutically effectiveamount of the chemotherapeutic drug from the film follows a delay periodof from 2 days to 14 days after the deploying the device in the tissuesite, wherein a sub-therapeutically effective amount of the drug or nodrug is released during the delay period, and wherein the delay periodis controlled solely by the in vivo degradation of thepoly(lactic-co-glycolic acid) in the tissue site.
 12. The method ofclaim 11, wherein deploying the drug-eluting device comprises implantingthe device in the patient in an open surgical procedure orlaparoscopically.
 13. The method of claim 12, wherein the tissue site isa biliary or pancreatic duct and the device is configured to preventclosure of the duct in which it is deployed.
 14. The method of claim 11,wherein the release of the therapeutically effective amount of thechemotherapeutic drug, after the delay period, has an initial releaserate that is substantially linear for at least 3 days.
 15. The method ofclaim 11, wherein the delay period is from 2 to 4 days.
 16. The methodof claim 11, wherein the in vivo degradation of thepoly(lactic-co-glycolic acid) is hydrolytic degradation.
 17. The methodof claim 11, wherein the chemotherapeutic drug is selected from thegroup consisting of paclitaxel, gemcitabine, nab-paclitaxel,5-fluorouracil, oxaliplatin, irinotecan, and combinations thereof. 18.The method of claim 11, wherein the chemotherapeutic drug is paclitaxel.19. The method of claim 18, wherein the therapeutically effective amountof the paclitaxel released is at least about 1 mg/day.
 20. The method ofclaim 18, wherein the therapeutically effective amount of the paclitaxelreleased is at a mean average amount of from 5 mg/day to 125 mg/day. 21.The method of claim 18, wherein the therapeutically effective amount ofpaclitaxel is released over a treatment period from about 10 days toabout 90 days.
 22. The method of claim 11, wherein the mixture comprisesfrom about 1 wt % to about 10 wt % of paclitaxel.
 23. The method ofclaim 11, wherein the degradable polymer is configured to degrade withina period from about 2 days to about 12 months after deployment,deploying a drug-eluting device into a tissue site of the pancreas,biliary system, gallbladder, liver, small bowel, or colon of a patientin need of treatment, the device comprising: a film which comprises amixture of a degradable polymer, which consists ofpoly(lactic-co-glycolic acid), and paclitaxel distributed in thedegradable polymer via solvent evaporation of a solution of thepaclitaxel and the degradable polymer, wherein the film has a thicknessfrom about 2 μm to about 1000 μm and is configured to release at leastabout 1 mg/day of the paclitaxel from the film by in vivo degradation ofthe polymer upon deployment at the tissue site; and a biocompatiblesubstratum to which the film is adhered, the substratum comprising astent; and releasing at least about 1 mg/day of the paclitaxel from thefilm, for at least 30 days, to treat the tumor, by in vivo degradationof the polymer in the tissue site.
 24. The method of claim 1, wherein nochemotherapeutic drug is released from the film during at least aportion of the delay period.
 25. The method of claim 11, wherein nochemotherapeutic drug is released from the film during at least aportion of the delay period.
 26. The method of claim 11, wherein thefilm is a smooth, nonporous composition.
 27. The method of claim 11,wherein the method results in at least a twofold increase in tumorreduction relative to systemic intravenous treatment at an identicaldosage of the chemotherapeutic drug.